The present invention is directed to derivatives of taxol which have improved water solubility as compared to taxol, and exhibit excellent antitumor activity. The compounds are particularly useful for the treatment of the same cancers for which taxol has been shown active, including human lung tumors, melanoma, leukemia, mammary tumors, and colon cancer.
Taxol is a known diterpenoid, sesquiterpene which was originally isolated from the stem bark of the western yew, Taxus brevifolia, and has the following structure: ##STR3## Taxol has been shown to possess potent antitumor activity against a wide variety of tumors. This compound, however, is only very slightly soluble in water and this has created significant problems in developing suitable pharmaceutical formulations useful for human therapy. Some formulations of taxol for injection or I.V. infusion have been developed primarily utilizing cremophore EL.RTM. as the drug carrier to overcome the low water solubility problems of taxol. Cremophore, however, is itself somewhat toxic causing idiosyncratic histamine release and anaphylactoid like response, so the use of this carrier is not a desirable solution to the problem of developing good formulations of taxol.
The present inventors, therefore, have investigated the development of derivatives of taxol which would be more water soluble than taxol, but would also exhibit the same or similar excellent antitumor and cytotoxic activity of taxol.